Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence.

Published online

Journal Article

BACKGROUND: Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur. METHODS: We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-Aβ antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with Aβ vaccination for 4 months. RESULTS: There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-Aβ immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. CONCLUSIONS: Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.

Full Text

Duke Authors

Cited Authors

  • Wilcock, DM; Morgan, D; Gordon, MN; Taylor, TL; Ridnour, LA; Wink, DA; Colton, CA

Published Date

  • September 9, 2011

Published In

Volume / Issue

  • 8 /

Start / End Page

  • 115 -

PubMed ID

  • 21906275

Pubmed Central ID

  • 21906275

Electronic International Standard Serial Number (EISSN)

  • 1742-2094

Digital Object Identifier (DOI)

  • 10.1186/1742-2094-8-115

Language

  • eng

Conference Location

  • England